The major objective of the proposed research is to examine the development of the neuromuscular system in a mouse model in which programmed cell death (PCD) of motoneurons has been eliminated by genetic deletion of pro-apoptotic genes. The use of this model will allow us to address issues of basic biology such as the adaptive significance of PCD in the nervous system and whether excess neurons can be functionally incorporated into the developing nervous system. Neuroanatomical, physiological and behavioural methods will be employed to examine both spinal and cranial motoneurons. We well determine whether rescued neurons differentiate normally; and whether physiological and behavioural assays of neuromuscular function are affected by the presence of tens of thousands of rescued motoneurons. Additionally, we plan to take advantage of the fact that even following injury, motoneurons in these mice can survive. Accordingly, we will cross these mice with a mouse model of Amyotrophic Lateral Sclerosis (ALS), the SOD1 mutant, and determine whether the pathological signs of motoneuron disease are ameliorated. In both the developmental and SOD1 studies, treatment with neurotrophic factors (NTFs) will be used in an attempt to optimize the development and maintenance of the neuromuscular system. The use of mice lacking motoneuron cell death provides a unique opportunity to examine: (1) the widely accepted but largely untested assumption that the PCD of neurons during development subserves essential adaptive functions that if perturbed would result in neurobehavioral dysfunction; and (2) the role of PCD and neurotrophic factors in a mouse model of ALS.